Pancreas cancer kills almost 30,000 Americans each year, due both to local progression and to metastatic disease. We have pioneered the concept of maximizing systemic therapy, while incorporating high dose conformal radiation for the locally advanced unresectable tumor. We have built a series of translational studies starting with the combination of gemcitabine and radiation followed by trials combining gemcitabine-radiation with additional chemotherapy. These latter trials produced somewhat better survival than were obtained by gemcitabine-radiation alone but also more toxicity. We hypothesize that the addition of molecularly targeted therapies to gemcitabine and radiation will increase efficacy without a substantial increase in toxicity. Our parent grant focuses on adding EGFR inhibition to gemcitabine-radiation. In this competitive revision, we propose to investigate the potential of a Chk1 (checkpoint kinase 1) inhibitor, AZD7762 (currently in Phase I trials), to improve gemcitabine-radiation therapy. Chk1 is a key regulator of DNA damage-induced cell cycle checkpoints and DNA repair;inhibition of Chk1 has been shown to sensitize to chemotherapy as well as to radiation. Specific Aim 1 is to determine the contributions of cell cycle checkpoints and homologous recombination repair to the mechanisms of AZD7762-mediated sensitization to radiation alone and to gemcitabineradiation. Specific Aim 2 is to determine the optimal schedule of administration of AZD7762, gemcitabine, and radiation in vivo in order to establish a basis for conducting a clinical trial. Because pre- and post-treatment tumor biopsies are not feasible in patients with pancreatic cancer, in Aim 2b we will develop assays in surrogate tissues to assess Chk1 inhibition. The long term goal of this research is to initiate a clinical trial combining AZD7762 with gemcitabine-radiation in pancreatic cancer, which we anticipate will begin shortly after the end of this funding period. PUBLIC HEALTH RELEVANCE: Pancreas cancer treated with the best available therapies has an average survival of approximately one year. In this application we propose to combine a new agent with the standard regimen of gemcitabine and radiation therapies. Our goal is to produce preclinical data which will facilitate the design of future clinical trials, ultimately leading to improved survival for patients with pancreatic cancer.